MXPA00006185A - Molecular dispersion composition with enhanced bioavailability - Google Patents

Abstract

A molecular dispersion composition is disclosed. The molecular dispersion comprises a compound of formula (I) molecularly dispersed in a polymer matrix. Also disclosed are solid dosage forms, e.g., tablets and capsules, containing these molecular dispersions.

Description

COMPOSITION FOR MOLECULAR DISPERSION WITH INCREASED BIOAVAILABILITY BACKGROUND OF THE INVENTION The present invention relates to compositions having an increased or improved bioavailability for a novel tricyclic amide compound. WO 97/23478 published July 3, 1997, describes useful tricyclic amides for the inhibition of G protein function and for the treatment of proliferative diseases. It was discovered that a particular compound, (+) - 4- [4- (8-chloro-3,10-dibromo-6,1-dihydro-5H-benzo [5,6-cyclohepta [1,2-b] pyridine- 1 1 -yl) -1-piperidinyl] -2-oxoethyl] -1-piperidinecarboxamide (Compound I) Enantiomer (+) - has a potent activity to inhibit the abnormal growth of cells, and to inhibit the famesyl-protein transferase. WO 97/23478 describes that examples of suitable compositions of this compound include solid compositions such as, for example, tablets and capsules. In developing a solid dose form, e.g., a tablet or capsule, it was found that crystalline compound I had poor bioavailability, and did not appear to be suitable for development as a tablet or capsule. The oral bioavailability of the active compounds may vary with the dosage form of the active compound. For example, it is known that solution and suspension dosages generally give rise to a higher bioavailability than capsules or tablets (see Pharmacokinetics Process and Mathematics, "ACS Monograph 185, Chapter 5, page"). 57 (1986), and JG Nairn, Remington's Phamaceutical Sciences, Eighteenth Edition (1990)). However, tablets and capsules are the most convenient dosage forms, and it would be preferable to obtain a tablet or capsule dosage form of an active compound having a bioavailability comparable to that of the solution or suspension. A formulation of compound I that provides increased bioavailability of the compound would be a welcome contribution in the art. A formulation of the above compound that can be prepared in the form of a tablet or capsule having a higher bioavailability, or a bioavailability comparable to that of a suspension would also be a Welcome contribution in the technique. This invention provides these contributions to the art. In this way, this invention solves the problem of making the active compounds having a very low bioavailability become a bioavailable form.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides a pharmaceutical composition comprising: a molecular dispersion, said molecular dispersion comprises a compound having the formula: Enantiomer (+) (i) molecularly dispersed in a polymeric matrix.

This invention also provides solid dosage forms comprising the molecular dispersion described above. Solid dosage forms include tablets, capsules and tablets chewable. The known excipients can be mixed with the molecular dispersion to provide the desired dosage form. For example, a capsule may contain the molecular dispersion mixed with (a) a disintegrant and a lubricant, or (b) a disintegrant, a lubricant and a surfactant. A tablet can contain the molecular dispersion mixed with at least one disintegrant, a lubricant, a surfactant and a glidant. The chewable tablet may contain the molecular dispersion mixed with a bulking agent, a lubricant and, if desired, an additional sweetening agent (such as, for example, an artificial sweetener), and suitable flavors.

DETAILED DESCRIPTION OF THE INVENTION The compound of the formula I is a tricyclic amide compound described in WO 97/23478, published on July 3, 1997. Reference to the "compound of the Formula I" also includes reference to the enantiomers of the compound. As used herein, the term "molecularly dispersed" or "molecular dispersion" refers to a condition in which: (a) the compound (I) has a substantially amorphous form and is dispersed in a polymer matrix (also known as " solid solution "), or (b) the compound (I) has the crystalline form and is dispersed in a polymeric matrix, the crystals are so fine that they can not be detected by means of the analysis of X-ray diffraction. As used herein, the t"substantially amorphous" refers to a condition wherein more than 90% of the compound (I) has the amorphous form. When the molecular dispersion is a dispersion of the compound (I) In the substantially amorphous form, these molecular dispersions can be prepared by dissolving the compound and a polymer in a suitable organic solvent, or mixture of organic solvents, and then removing the solvent to produce a molecular dispersion. The molecular dispersions formed in this manner are such that the compound (I) has the substantially amorphous form and is homogeneously dispersed in the polymer matrix. Preferably, the polymer is a water soluble polymer. When the insoluble polymers are used in place of water-soluble polymers, the resulting molecular dispersions have an increased bioavailability, but will exhibit a sustained release profile. Alternatively, the molecular dispersions can be prepared by dissolving the compound of the formula (I) in an organic solvent that will dilate a polymer matrix instead of dissolving the polymer. The polymeric matrix will absorb the active solution, offering the compound (I) in a crystalline or amorphous state dispersed in the matrix, after the subsequent evaporation of the solvent. The preparation of the solid solutions of the suitable polymers is known in the art, for example, on page 173 in Kollidon - polyvinylpyrrolidone for the pharmaceutical industry of BASF. The preparation of solid solutions of insoluble polymer matrices is also known in the art, and these preparations are similar to those for drug loading in crosslinked hydrogels, see for example, U.S. Patent No. 4,624,848 and Lee, PI, Kinectics. of Drug Relase from Hydrogel Matrices ("Kinetics of drug release from hydrogel matrices"), Journal of Controlled Relay, Vol. II, pages 277 through 288 (nineteen ninety five). Water-soluble polymers suitable for use as a polymeric matrix include, but are not limited to: polyvinylpyrrolidone (Povidone); hydroxypropyl methyl cellulose, hydroxypropyl cellulose; polyethylene glycol; polyethylene oxide; jelly; carbomer; carboxymethyl cellulose; methyl cellulose; methacrylic acid copolymer; ammonium methacrylate copolymer; hydroxyethyl cellulose; polyvinyl alcohol; cellulose acetate phthalate; hydroxypropyl methylcellulose phthalate; and polyvinyl alcohol phthalate. Water-insoluble polymers suitable for use as a polymeric matrix include, but are not limited to: crospovidone; Sodium starch glycolate; and croscarmellose. Preferably the polymer used for the polymer matrix is selected from the group consisting of polyvinylpyrrolidone (Povidone), hydroxypropyl methylcellulose, hydroxypropyl cellulose and polyethylene glycol. Polyvinylpyrrolidone is particularly preferred. When a water insoluble polymer is used, crospovidone is preferred.

All of the above polymers are known in the art. The polyvinyl pyrrolidone represents the polymers of 1-vinyl-2-pyrrolidone. It is commercially available as Povidone or Kollidon with an average weight between about 12,000 and 150,000. Generally, the polyvinylpyrrolidone used has an average weight within a range between about 7,000 and about 54,000, preferably between about 28,000 and about 54,000, and more preferably between about 29,000 and about 44,000. Crospovidone represents the synthetic insoluble crosslinked homopolymers of N-vinyl-2-pyrrolidone. Generally, crospovidone has a particle size of between about 20 μM and about 250 μM, and preferably between 50 μM and about 250 μM (see, for example, Kollidon, polyvinylpyrrolidone for the pharmaceutical industry of BASF). Preferably, the ratio between the compound of the formula (I) and the polymer is between about 1: 0.5 and about 1: 4., more preferably between about 1: 1 and about 1: 3 and more preferably, about 1: 1. When the molecular dispersions of the present invention are prepared by dissolving the compound of the formula I and the polymer in an organic solvent or mixture of organic solvents, suitable organic solvents include, but are not limited to, methylene chloride, methanol, ethanol, sopropanol, tetrahydrofuran or their mixtures. The solvent can be removed by means of the methods conventional for example, evaporating the solvent under a hood; use the double drum dryer or the spray dryer or supercritical fluid extraction process. The composition comprising the molecular dispersion may, optionally, further comprise excipients selected from the group consisting of: disintegrants, lubricants, surfactants, glidants, artificial sweeteners, bulking agents, colorants and one or more flavorings. Generally, compound I is within a range between 15 and 60% in formulations (tablets, capsules, or powders). Generally, the composition comprising the molecular dispersion can, optionally, comprise: between about 5 and about 40% by weight of one or more disintegrants, about 0.1 and about 1% by weight of one or more lubricants, between about 3 and about 15% by weight of one or more surfactants, between about 0.1 and about 5% by weight of one or more glidants, about 0.1 and about 1% by weight of one or more artificial sweeteners , between about 25 and about 75% of one or more bulking agents, between about 0.1 and about 1% by weight of one or more colorants (coloring agents), and / or between about 0.1 and about 1 % by weight of one or more flavorings (flavoring agents). Suitable disintegrants are selected from the group consisting of: croscarmellose sodium (a crosslinked polymer of carboxymethylcellulose) sodium, see NF XVII page 1922 (1990)), crospovidone, NF starch, polacrilin sodium or potassium glycolate and sodium starch glycollate. Preferably, croscarmellose sodium is used as a disintegrant in the capsule compositions. Preferably, crospovidone is used as a disintegrant in the compressible tablets. Those skilled in the art will appreciate that it is convenient for compressible tablets to disintegrate within 30 minutes; therefore, the disintegrant used preferably causes the disintegration of the tablet within 30 minutes. It has been found that disintegrants, such as croscarmellose sodium and crospovidone, used in amounts of less than 30% by weight do not produce tablets that disintegrate within 30 minutes. It is believed that significantly higher amounts of these disintegrants will cause the tablet to disintegrate within 30 minutes. Suitable lubricants include talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils and the like. Preferably, magnesium stearate is used. Suitable surfactants include block copolymers of ethylene oxide and propylene oxide such as, for example, Pluronic® F-68 (Poloxamer 188), Pluronic® F87 (poloxamer 237), Pluronic® F108 (Poloxamer 338), Pluronic® F12 (Poloxamer 407 ) and similar. Preferably, Pluronic.RTM. F-68 is used. According to the Corporation's Technical Bulletin of BASF (Technical Bulletin of the BASF Corporation (1995), Pluronic® is a registered trade name for the block copolymers of ethylene oxide and propylene oxide represented by the structure HO (C2H4O) to (C3H6O) b (C2H4O) ar-l where for: (a) Pluronic® F-68, a is 80 and b is 27; (b) Pluronic R F87, a is 64 and b is 37; (c) Pluronic.RTM. F108, a is 141 and b is 44; and Pluronic® F127, a is 101 and b is 56. The average molecular weights of these block copolymers are 8,400, 7,700, 14,600 and 12,600 for Pluronic F-68, Pluronic-F87, Pluronic F108 and Pluronic F127, respectively. Suitable glidants include silicon dioxide, talc and the like. Preferably, silicon dioxide is used. Suitable bulking agents include xylitol, mannitol, compressible sugars, lactose and microcrystalline celluloses. Preferably, xylitol is used for chewable tablets. Suitable artificial sweeteners include saccharin, cyclamates and aspartame. If desired, the known flavors and dyes FD &; C known can be added to the composition. The composition comprising the molecular dispersion can be produced in the solid dosage forms. Solid dosage forms include capsules (e.g., soft gelatin capsules and hard gelatin capsules), tablets (including, for example, coated tablets, gel coated tablets and coated enteric tablets) and chewable tablets. These dosage forms can be produced by methods known in the art, see for example, Lachman et al. al., The Theory and Practice of Industrial Pharmacy, ("The theory and practice of industrial pharmacy"), Second Edition, Read & Febiger, Philadelphia, pages 321-344 and pages 389-404 (1976). For dosage forms for capsules, the composition comprising a molecular dispersion generally comprises disintegrants, lubricants, and optionally, surfactants. In this way, a composition for use in capsules can comprise between about 65 and about 90% by weight of the molecular dispersion, between about 5% by weight of one or more disintegrants, between about 0.2 and about of 1% by weight of one or more lubricants, about 1-3% of glidant, and optionally between about 3 and about 15% by weight of one or more surfactants. For example, a composition for use in a capsule dosage form comprises: between about 80 and about 85% by weight of the molecular dispersion, between about 5 and about 10% by weight of one or more disintegrants, between about 0.5 and about 1% by weight of one or more lubricants, between about 0.5 and about 1.5% by weight of the glidant and between about 3 and about 15% of the surfactant. Another example of a composition for use in a dosage form for capsules is a composition comprising between about 70 and about 85% by weight of the molecular dispersion, between about 5 and about 20% by weight of one or more disintegrants, between about 0.3 and about 1% by weight of one or more lubricants, and between about 5 and about 15% by weight of one or more surfactants and 1-3% of the glidant. In general, the compositions for capsule dosage forms contain the molecular dispersion, a disintegrant, a lubricant, a glidant and optionally, a surfactant. Preferably, the disintegrant in the capsule composition is croscarmellose sodium. For the dosage form for compressible tablet, the composition comprising the molecular dispersion generally further comprises disintegrants, lubricants, surfactants and glidants. In this way, a composition for use in compressible tablets may comprise between about 50 and about 75% by weight of the molecular dispersion, between about 20 and about 45% by weight of one or more disintegrants, preferably, between about of 28 and about 35% by weight of one or more disintegrants, between about 0.2 and about 1% by weight of one or more lubricants, between about 4 and about 10% by weight of one or more surfactants, and between about 0.2 and about 0.6% by weight of one or more glidants. Preferably, the disintegrant is crospovidone. More preferably, the disintegrant is crospovidone in an amount between about 8 and about 40% by weight. More preferably, the disintegrant is crosvidone in an amount between about 25 and about 35% by weight and the other disintegrant (preferably croscarmellose sodium) is used. in amounts between about 8 and about 25% by weight. When used as a disintegrant, crospovidone generally has a particle size between about 20 μM and about 250 μM, with between about 50 μM and about 250 μM being preferred. In addition to the disintegrant, the compressible tablet also preferably comprises a lubricant, a surfactant and a glidant. For chewable tablets, the composition generally comprises between about 20 and about 50% by weight of the molecular dispersion, between about 78 and about 98% by weight of a bulking agent (for example, a sugar such as , xylitol), and between about 0.2 and about 1% by weight of a lubricant, optionally between about 0.2 and about 1% by weight of an artificial sweetener (eg, sodium saccharin or aspartame), and optionally between about 0.2 and about 1% by weight of a colorant. A preferred composition for tablets comprises: (1) about 58.8% by weight of a molecular dispersion comprising (a) a compound of Formula I and (b) povidone, wherein the ratio of said compound and said polymer is about eleven; (2) about 32.6% by weight of croscarmellose sodium (disintegrant); (3) or about 32.6% by weight of the crospovidone (disintegrant); (4) about 0.3% by weight of magnesium stearate (lubricant); (5) about 7.04% by weight of Pluronic® F-68 (surfactant); and about 0.9% by weight of silicon dioxide (slip). More preferably, povidone has a molecular weight between about 29,000 and about 44,000. A preferred composition is illustrated in the following Examples.

DOSING PROTOCOL FOR MONKEYS The formulation to be tested was administered orally to male Cynomolgus monkeys in a single dose (PO, simple). The number of monkeys for each test is indicated by the letter "N" followed by an equal sign and a number. In this way "(N = 6)" means that the formulation was administered to six monkeys. The total amount of the compound of formula I administered was 100 to 200 mg given in a capsule or tablet containing 100 or 200 mg each. The dose administered (tablet, capsule or control suspension) was slowly washed with 10 ml of water. Blood samples were taken at 15, minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours and 48 hours in heparinized syringes. Plasma was obtained for the analysis by centrifugation to 4 ° C. The plasma samples (one for each point in time) were divided and stored at -20 ° C until tested in the manner described below. The treated monkeys were fed two biscuits on the morning of the day of administration of the drug. No food was given to the monkeys during the night before the administration of the drug and were fed normally after 4 hours after the administration of the drug.

Bioavailability test Plasma samples were collected from the monkeys at selected time intervals. The plasma was analyzed by means of a high pressure liquid chromatographic (HPLC) procedure with ultraviolet detection. The AUC values (area under the plasma concentration-time curve, 0-72 hours) were calculated using standard procedures to determine the relative bioavailability of the compound in the formulations tested. The higher the AUC value, the greater the bioavailability. A suspension of the compound of Formula I was used as control. The control was prepared by suspending sufficient compound of Formula I in a solution of methyl cellulose to provide a dose of 30 mk / kg of body weight of the monkey. The 0.4% methyl cellulose solution was prepared by adding 4 grams of methyl cellulose to one liter of distilled water and heated to 80 ° C with stirring for about 1 VT. hours. The results of the bioavailability test are given in terms of percentage relative bioavailability (AUC ratio) compared to the amorphous suspension of Compound I in a 0.4% methyl cellulose solution.

EXAMPLE 1 Preparation of molecular dispersion Composition G / lot% composition Crystalline Compound I 25 Povidone NF K29 / 32 21 75 Methylene Chloride 1,000 ml evaporates The crystalline compound I and povidone were dissolved in methylene chloride. The solvent was evaporated under a hood and then the residue was dried under a suitable vacuum. The residue was then reduced in fine particles by grinding. The powder was then passed through a 30 mesh screen. The powder was found to be amorphous by X-ray analysis.

EXAMPLE 2 Preparation of molecular dispersion Composition G / lot% composition Crystalline Compound I 33 33.3 Povidone NF K29 / 32 20 66.6 Methylene Chloride 50 ml evaporate The crystalline compound I and povidone were dissolved in methylene chloride. The solvent was evaporated under a hood and then the residue was dried under a suitable vacuum. The residue was then reduced in fine particles by grinding. The powder was then passed through a 30 mesh screen. The powder was found to be amorphous by X-ray analysis.

EXAMPLE 3 Preparation of molecular dispersion Composition G / lot% composition Crystalline Compound I 50 50 Povidone NF K29 / 32 5 50 Methylene Chloride 300 ml evaporates The crystalline compound I and povidone were dissolved in methylene chloride. The solvent was evaporated from a hood and then the residue was dried under a suitable vacuum. The residue was then reduced in fine particles by grinding. The powder was then passed through a 30 mesh screen. The powder was found to be amorphous by X-ray analysis.

EXAMPLE 4 Preparation of molecular dispersion Composition G / lot% composition Crystalline Compound I 25 Povidone NF K29 / 32 30 75 Methylene Chloride 140 ml Evaporate Methanol 60 ml e Va ñora The crystalline compound I and povidone were dissolved in methylene chloride and methanol. The solvent was evaporated under a hood and then the residue was dried under a suitable vacuum. The residue was then reduced in fine particles by grinding. The powder was then passed through a 30 mesh screen. The powder was found to be amorphous by X-ray analysis.

EXAMPLE 5 Preparation of molecular dispersion Composition G / lot% composition Crystalline Compound I 7.5 33.3 Povidone NF K29 / 32 15 66.6 Methylene chloride 140 ml evaporate Methanol 60 ml evanora Crystalline compound I and povidone were dissolved in methylene chloride and methanol. The solvent was evaporated under a hood and then the residue was dried under a suitable vacuum. The residue was then reduced in fine particles by grinding. The powder was then passed through a 30 mesh screen. The powder was found to be amorphous by X-ray analysis.

EXAMPLE 6 Preparation of molecular dispersion Composition G / batch% of the composition Crystalline Compound I 15 50 Povidone NF K29 / 32 15 50 Methylene chloride 140 ml evaporate Methanol 60 ml evaporate The crystalline compound I and povidone were dissolved in methylene chloride and methanol. The solvent was evaporated under a hood and then the residue was dried under a suitable vacuum. The residue was then reduced in fine particles by grinding. The powder was then passed through a 30 mesh screen. The powder was found to be amorphous by X-ray analysis.

EXEMPLC) 7 Preparation of molecular dispersion Composition G / lot% composition Crystal compound I 80 25 Povidone NF K29 / 32 30 75 Methylene chloride 140 ml evaporate The crystalline compound I and povidone were dissolved in methylene chloride. The solvent was removed using a double drum dryer. The residue was then reduced in fine particles by grinding. The powder was then passed through a 30 mesh screen. The powder was found to be amorphous by X-ray analysis.

EXAMPLE 8 Preparation of molecular dispersion Composition G / lot% composition Crystal Compound I 80 25 Povidone NF K29 / 32 240 75 Methylene Chloride 5,000 ml evaporates The crystalline compound I and povidone were dissolved in methylene chloride. The solvent was removed using a double drum dryer. The residue was then reduced in fine particles by medium. The powder was then passed through a 30 mesh screen. The powder was found to be amorphous from the X-ray analysis.

EXAMPLE 9 Preparation of molecular dispersion The solution of Example 7 was dried using a drum suitable for solvent spraying.

EXAMPLE 10 Preparation of molecular dispersion The solution of Example 8 was dried using a drum suitable for solvent spraying.

EXAMPLE 11 Preparation of molecular dispersion The solution of Example 6 was dried using a drum suitable for solvent spraying.

EXAMPLE 12 Formulation of the capsule Composition Mq / capsule% composition Molecular dispersion 400 84.2 of example 1 Pluronic F68 NF 25 5.2 Croscarmellose sodium 42.5 8.9 NF Silicon dioxide NF 5 1.1 Stearate of 2.5 0.6 mg NF TOTAL 475 Size of capsule Nr.O Method The molecular dispersion of Example 1, Pluronic, croscarmellose sodium, and silicon dioxide were mixed in a suitable mixer for 10 minutes. A premix was formed with the magnesium stearate and an equal portion of the mixture. The premix was added to the mixture and the resulting mixture was mixed for an additional 5 minutes. The mixture was encapsulated in hard layer gelatin capsules Nr. 0.

EXAMPLE 13 Formulation of the capsule Composition Mg / capsule% of the composition Molecular dispersion 200 72.7 of example 6 Pluronic F68 NF 25 9.1 Croscarmellose sodium 42.5 15.5 NF Silicon dioxide NF 5 1.8 Stearate 2.5 0.9 mg NF TOTAL 275 Capsule size Nr.2 Method The molecular dispersion of Example 6, Pluronic, croscarmellose sodium, and silicon dioxide were mixed in a suitable mixer for 10 minutes. A premix was formed with the magnesium stearate and an equal portion of the mixture. The premix was added to the mixture and the resulting mixture was mixed for an additional 5 minutes. The mixture was then encapsulated in Nr. 2 hard shell gelatin capsules.

EXAMPLE 14 Formulation of the capsule Composition Ma / capsule% composition Molecular dispersion 200 80 of example 6 Pluronic F68 NF 25 10 Croscarmellose sodium 20 8 NF Silicon dioxide NF 3.75 1.5 Stearate of 1.25 0.5 mg NF TOTAL 250 Size of the capsule Nr.2 Method The molecular dispersion of Example 6, Pluronic, croscarmellose sodium, and silicon dioxide were mixed in a suitable mixer for 10 minutes. A premix was formed with the magnesium stearate and an equal portion of the mixture. The premix was added to the mixture and the resulting mixture was mixed for an additional 5 minutes. The mixture was then encapsulated in Nr. 2 hard shell gelatin capsules.

EXAMPLE 15 Preparation of the capsule Composition Mq / capsule% of the composition Molecular dispersion 400 80 of example 6 Pluronic F68 NF 50 10 Croscarmellose sodium 40 8 NF Silicon dioxide NF 7.5 1.5 Stearate 2.5 0.5 mg NF TOTAL 500 Size of capsule Nr.O Method The molecular dispersion of Example 6, Pluronic, croscarmellose sodium, and silicon dioxide were mixed in a suitable mixer for 10 minutes. A premix was formed with the magnesium stearate and an equal portion of the mixture. The premix was added to the mixture and the resulting mixture was mixed for an additional 5 minutes. The mixture was then encapsulated in gelatin capsules with a hardness of Nr. 0.

EXAMPLE 16 Tablet formulation Composition Mq / tablet% composition Molecular Direction of Example 4 40000 66.7 4 Pluronic F68 25 4.2 Croscarmellose sodium NF 167.5 27.9 Silicon dioxide 5 0.8 Magnesium stearate 2.5 0.4 TOTAL 600 Method The molecular dispersion of Example 4, Pluronic, croscarmellose sodium, and silicon dioxide were mixed in a suitable mixer for 10 minutes. A premix was formed with the magnesium stearate and an equal portion of the mixture. The premix was added to the mixture and the resulting mixture was mixed for an additional 5 minutes. The mixture was then compressed into tablets using a machine formed of suitable tablets.

EXAMPLE 17 Formulation for tablet Composition Mq / tablet% composition Molecular Direction of Example 300 66.7 5 Pluronic F68 25 5.5 Crospovidone NF 30 6.7 Croscarmellose sodium NF 89 19.8 Silicon dioxide 4 0.9 Magnesium stearate 2 0.4 TOTAL 450 Method The molecular dispersion of Example 5, Pluronic, croscarmellose sodium, and silicon dioxide were mixed in a suitable mixer for 10 minutes. A premix was formed with the magnesium stearate and an equal portion of the mixture. The premix was added to the mixture and the resulting mixture was mixed for an additional 5 minutes. The resulting mixture was then compressed into tablets using a suitable tabletting machine.

EXAMPLE 18 Formulation for tablet Composition Mq / tablet% composition Molecular Direction of Example 2 20000 58.8 6 Pluronic F68 25 7.4 Crospovidone NF 110.75 32.6 Silicon Dioxide 3 0.9 Magnesium Stearate 1.25 0.3 TOTAL 340 Method The molecular dispersion of Example 6, Pluronic, croscarmellose sodium, and silicon dioxide were mixed in a suitable mixer for 10 minutes. A premix was formed with the magnesium stearate and an equal portion of the mixture. The premix was added to the mixture and the resulting mixture was mixed for an additional 5 minutes. The mixture was then compressed into tablets using a suitable tablet-forming machine.

EXAMPLE 19 Formulation for tablet Composition Mq / tablet% composition Molecular Direction of Example 2 20000 58.8 6 Pluronic F68 25 7.4 Croscarmellose sodium NF 1 10.75 32.6 Silicon dioxide 3 0.9 Magnesium stearate 1.25 0.3 TOTAL 340 Method The molecular dispersion of Example 6, Pluronic, croscarmellose sodium, and silicon dioxide were mixed in a suitable mixer for 10 minutes. A premix was formed with the magnesium stearate and an equal portion of the mixture. The premix was added to the mixture and the resulting mixture was mixed for an additional 5 minutes. The resulting mixture was then compressed into tablets using a suitable tabletting machine.

EXAMPLE JO Y 21 Formulation for capsule Composition 20 21% mq / capsule mq / capsule composition Molecular dispersion of 100 400.0 84.2 Example 9 Silicon dioxide NF (1) 0.625 2.5 0.5 Magnesium stearate NF (:) 0.125 0.5 0.1 Croscarmellose sodium NF 1 1.000 44.0 9.3 Pluronic F68 NF 6.250 2.5 0.5 Silicon dioxide NF (J) 9m625 2.5 0.5 Magnesium stearate NF (4) 0.125 0.5 0.1 TOTAL 1 18.750 475.000 Capsule size Nr 4 Nr. O Method The molecular dispersion of Example 9, silicon dioxide (1) and magnesium stearate were mixed in a suitable mixer for 10 minutes. The mixture was compacted using a suitable compact roller and ground using a suitable mill with a 30 mesh screen. Croscarmellose sodium, Pluronic F68 and silicon dioxide were added. { 3) to the ground mixture and mixed another 10 minutes. Another premix was prepared with the magnesium stearate (4) and an equal portion of the mixture. The premix was added to the rest of the mixture and mixed for 5 minutes. The mixture was encapsulated in a hard shell gelatin capsule.

EXAMPLE 22 AND 23 Formulation for capsule Method The molecular dispersion of example 11, silicon dioxide (1) and magnesium stearate (2) were mixed in a suitable mixer for 10 minutes. The mixture was compacted using a suitable compact roller and milled using a suitable mill with a 30 mesh screen. Croscarmellose sodium, Pluronic F68 and silicon dioxide (3) were added to the ground mixture and mixed for another 10 minutes. Another premix was prepared with the magnesium stearate (4) and an equal portion of the mixture. The premix was added to the rest of the mixture and mixed for 5 minutes. The mixture was encapsulated in a hard shell gelatin capsule.

EXAMPLE 24 AND 25 Formulation for capsule Method Mix the molecular dispersion of Example 1 1 with the xylitol in a suitable mixer for 10 minutes. Prepare a premix of flavor, color and a portion of the mixture, pass through a 30 mesh screen. Add the premix to the rest of the mixture and mix for an additional 10 minutes. Pass through the 30 mesh screen. Add the premix to the rest of the mixture and mix for 5 minutes. The resulting mixture was compressed into tablets using a tablet-forming machine.

EXAMPLE 26 Formulation for tablet Composition G / batch% composition Compound I 8.0 25 Polyethylene glycol 8000 NF 24.0 75 Methylene chloride 5000 ml The crystalline compound I and the polyethylene glycol 8000 were dissolved in methylene chloride and the solvent was removed in a hood and then the residue was further dried under a suitable vacuum. The residue was then reduced to fine particles by grinding. The powder was then passed through a 30 mesh screen. The powder was found to be amorphous by X-ray analysis.

EXAMPLE 27 Formulation for capsule Composition G / lot% composition Molecular dispersion of example 26 400 84.2 Pluronic F68 NF 25 5.2 Croscarmellose sodium NF 42.5 8.9 Silicon dioxide NF 5 1.1 Magnesium stearate NF 2.5 0.6 TOTAL 475 Size of capsule Nr.O Method The molecular dispersion of Example 26, the pluronic, was mixed F68, croscarmellose sodium and silicon dioxide in a suitable mixer for 10 minutes. A premix was formed with the magnesium stearate and an equal portion of the mixture. The premix was added to the mixture and the resulting mixture was mixed for an additional 5 minutes. The mixture was encapsulated in a Nr.O hard shell gelatin capsule. The bioavailability of the compound of the formula I was extremely poor and the development of a solid dosage form by the use of conventional excipients was not successful. The formulations containing the molecular dispersions of this invention were prepared and compared with a control composition formed by a suspension of the compound of the formula I. The relative bioavailability of the suspensions of the crystalline form of the compound I was prepared and compared to a suspension of the amorphous form of compound I in fasting or fed male cynomolgus monkeys. The relative bodysponibility of the suspensions containing the crystalline compound I was 1.3% of the AUC and 2.7% of the Cmax of the suspensions containing the amorphous form of compound I. In the fed monkeys, the relative bioavailability of the suspensions of compound I was 3.6% of the AUC and 5.2% of the C max of the suspensions containing the amorphous form of the compound I. The relative bioavailability of the formulations containing molecular dispersions of this invention is determined in monkeys fed using as a comparison the suspensions containing the amorphous compound I.

Claims (10)

NOVELTY OF THE INVENTION CLAIMS

1. A pharmaceutical composition comprising: a molecular dispersion, said molecular dispersion comprises a compound having the formula: Enantiomer (+) -molecularly dispersed in a polymeric matrix.

2. The pharmaceutical composition of claim 1, wherein the polymer matrix comprises a polymer that is soluble in water.

3. The pharmaceutical composition of claim 2, wherein the polymer is selected from the group consisting of: polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, and polyethylene glycol.

4. The pharmaceutical composition of claim 3, wherein the ratio of said compound to said polymer is about 1: 0.5 and around 1: 4

5. The pharmaceutical composition of claim 4, wherein said polymer is polyvinylpyrrolidone.

6. The pharmaceutical composition of claim 5, wherein the ratio of said compound to said polymer is about 1: 1 and about 1: 3.

7. The pharmaceutical composition of claim 8, characterized in that the ratio of said compound to said polymer is about 1: 1.

8. A tablet characterized in that it comprises: (A) between about 50 and about 75% of a molecular dispersion, said molecular dispersion comprises a compound of claim 1 having the formula Enantiomer (+) - molecularly dispersed in a polymeric matrix; (B) between about 5 and about 40% by weight of a disintegrant; (C) between about 0.1 and about 1% by weight of a lubricant; (D) between about 3 and about 15% by weight of a surfactant; and (E) between about 0.1 and about 1% by weight of a glider.

9. The tablet of claim 9, characterized in that the polymer matrix comprises a polymer that is soluble in water. The tablet of claim 9, characterized in that the polymer is selected from the group consisting of: polyvinylpyrrolidone, hydroxypropyl methylceulose, hydroxypropyl cellulose and polyethylene glycol. The tablet of claim 10, characterized in that the ratio between said compound and said polymer is about 1: 0.5 and about 1: 4. The tablet of claim 10, characterized in that said polymer is polyvinylpyrrolidone. 13. A capsule comprising: (A) between about 65 and about 90% by weight of a molecular dispersion, said molecular dispersion comprising a compound having the formula: Enantiomer (+) molecularly dispersed in a polymeric matrix; (B) between about 5 and about 20% by weight of a disintegrant; (C) between about 0.2 and about 1% by weight of a lubricant; (D) between about 3 and about 15% by weight of a surfactant; and (E) between about 1 and about 3% by weight of a glider. The capsule of claim 13, wherein the polymer matrix comprises a polymer that is soluble in water. The capsule of claim 14, wherein the polymer is selected from the group consisting of: polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, and polyethylene glycol. The capsule of claim 15, wherein the ratio between said compound and said polymer is between about 1: 0.5 and about 1: 4. 17. The capsule of claim 16 wherein said polymer is polyvinylpyrrolidone.